Synthesis of steroids

ABSTRACT

THIS INVENTION RELATES TO NOVEL COMPOUNDS HAVING THE FORMULAE   1-BOOC-,3A,8A,10A-TRI-H3C-,9-R,9-R&#39;&#39;-1,2,3,3A,3B,4,6,7,8,   8A,8B,9,10,10A-TETRADECAHYDRODICYCLOPENTA(A,F)NAPHTHA-   LEN-6-ONE , 1-BOOC-,3A,8A,10A-TRI-H3C-,1,2,3,3A,3B,4,6,7   ,8,8A,10,10A-DODECAHYDRODICYCLOPENTA(A,F)NAPHTHALEN-6-   ONE, 1-BOOC-,3A,8A,10A-TRI-H3C-,9-R,9-R&#39;&#39;-1,2,3,3A,3B,4,   6,7,8,8A,8B,9,10,10A-TETRADECAHYDRODICYCLOPENTA(A,F)-   NAPHTHALENE-3,6-DIONE AND 1-BOOC-,3A,8A,10A-TRI-H3C-,   1,2,3,3A,3B,4,6,7,8,8A,10,10A-DODECAHYDRODICYCLOPENTA(A,   F)NAPHTHALENE-3,6-DIONE   WHEREIN B IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL; R IS HYDROGEN; R1 IS HYDROXY; AND TOGETHER R AND R1 IS OXO(O=). THESE COMPOUNDS ARE INTERMEDIATES FOR STEROIDS POSSESSING ANTI-ANDROGENIC ACTIVITY.

United States Patent US. Cl. 260-468F 4 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel compounds having the formulae wherein B is selected from the group consisting of hydrogen and lower alkyl; R is hydrogen; R is hydroxy; and together R and R is oxo(0=). These compounds are intermediates for steroids possessing anti-androgenic activity.

This application is a division of my application, Ser. No. 308,693, filed Sept. 13, 1963, now Patent No. 3,393,230.

This invention relates to and has for its objects the provision of new physiologically active steroids, methods for their production, and novel intermediates useful in the preparation thereof.

The novel final products of the instant invention may be represented by the formulae or m 3,600,425 Patented Aug. 17, 1971 ice wherein R is hydrogen; R is hydroxy; and together R and R is 0x0 (0 X is lower alkyl (e.g. methyl) and Z is selected from the group consisting of hydrogen, hydroxy, acyloxy and halogen (e.g. chloro, fiuoro, bromo or iodo).

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g. acetic, propionic, butyric and tert.-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g. benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g. phenacetic and fi-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The products of this invention are physiologically active compounds which possess antiandrogenic activity and thus may be employed in the treatment of hyperandrogenic acne, for which purpose they may be adminstered, the dosage being adjusted for the relative potency of the particular steroid and the requirements of the patient.

The final products of this invention may be prepared by the processes of this invention, which entail a number of steps starting with the compounds represented by the following formulae COOB COOB

do 0 b (5H. OQIQ/JH.

COOB

(IJOOB )3 Dog I COOB COOB R )1) ll n3 X 11:11; R=OH; A=halide 01,131 XII A=halide (Ol,Br) XI RdzR'=O=; A=halide (CLBr) ll-substituted Anor-A -androstenes (Compounds A) and the A-nor-A -androstadienes (Compounds B) starting materials are reacted with a diazoal-kane (e.g. diazomethane) in the presence of a metal halide (e.g. aluminum chloride) to yield the respective pyrazoline derivatives thereof (Compounds C and D) which are new compounds of this invention.

Compounds C and D may then be heated at temperatures above their respective melting points to yield the respective 6-methyl-A -androstene (Compounds E) and the 6-methyl-A -androstadienes (Compounds P), which are also new compounds of this invention.

Compounds E and F may then be treated with an acid halide, for example, oxalyl chloride, to obtain the corresponding ll-substituted 6-methyl-A-nor-A -androstenel7-carboxylic acid halides (Compounds G) and the 6- methyl-A-nor-A -androstadiene l7 carboxylic acid chlorides (Compounds H) respectively, which are also new compounds of this invention.

These acid chloride compounds (Compounds G and H) are then converted to their respective diazoketone-G- methyl-A-nor-A -pregnenes (Compounds J) and diazoketone-6-methyl-A-nor-A -pregnadienes (Compounds K), which are also new compounds of this invention, by treatment with an ethereal solution of diazomethane.

In order to obtain the final products of this invention which are oxygenated in the 21-position (i.e. Z is acyloxy or hydroxy). Compounds J and K are treated at elevated temperature with a fatty acid, for example, acetic, propionic or butyric acid, to yield the 21-esters of ll-substituted-6-methyl-A-nor-A -pregnenes (Compounds L) and 6-methyl-A-nor-A -pregnadienes (Compounds M), which are also new compounds of this invention. Alternatively, Compounds L and M (wherein Z is acyloxy) may be obtained by first treating Compounds J and K with a hydrohalide, for example, hydrochloric acid,

to yield the 21-halogenated-A-nor-pregnenes (Compounds L and M, wherein Z is halide), which are also new compounds of this invention, and then substituting the 21- halide-A-nor-pregnenes as by treatment with potassium iodide and potassium acetate to yield the respective 21- acyloxy-A-nor-pregnenes (Compounds L and M). To obtain the 2l-hydroxy-A-nor-pregnene compounds of this invention (Compounds L and M, wherein Z is hydroxy), the 2l-acyloxy compounds are treated with a base, such as potassium carbonate. The 21 hydroxy-6-methyl-A-norpregnenes (Compounds L and M, wherein Z is hydroxy) are also new compounds of this invention.

To obtain the final compounds of this invention, which are not oxygenated in the 2l-position (i.e. wherein Z is hydrogen or halogen), Compounds J and K are first treated with hydriodic acid to yield the Zl-unsubstituted- A-nor-pregnenes (Compounds L and M, wherein Z is hydrogen), which are also new compounds of this invention.

The 2l-halogenated compounds are obtained as set forth hereina bove, i.e., by treatment of Compounds 1 and K with a hydrohalide, e.g., hydrochloric acid. It should be noted that when the l-keto starting materials are employed in the practice of this invention, the final products thereof and the intermediates produced thereby will all be the l5-keto derivatives of the compounds set forth hereinabove. These compounds are also new compounds of this invention.

The invention may be further illustrated by the following examples:

EXAMPLE 1 Methyl 14-methyl-5,6-pyrazolino-A-norandrostane-3,l1- ,dione-l7fi-carboxylate (II) To a suspension of 59 mg. of finely powdered methyl l4-methyl-A-nor-A androstene-3,ll-dione 17,8 carboxylate (I) in 30 ml. of ethereal diazomethane solution is added at room temperature, in portions, a total of mg. of aluminum chloride which had been aged by leaving it exposed to the atmosphere for 510 minutes. The total reaction time is one hour and thirty minutes. The excess diazornethane is then destroyed by the addition of two drops of glacial acetic. The mixture is washed with water and the ether extract evaporated to dryness in vacuo. The resulting residual mixture is purified by preparative thin layer chromatography on activity V neutral alumina using chloroform: as the moving phase. Two zones are obtained, designated as A and B. The elution of zone A furnishes after concentration 21 mg. of material, M.P. 20020l, which is identified as starting material. Elution of zone B furnishes after crystallization from methanol 9 mg. of methyl 14-methyl-5,6-pyrazoliuo-A-norandrostane-3,1l-dione-l7fl-carboxylate which melts with decomposition at 176l78; [a] ]-36O (c., 0.28 in chloroform);

m 5.79, 5.87, 6.53 Analysis.Calcd. for C H O N (386.48) (percent): C, 68.37; H, 7.82. Found (percent): C, 68.43; H, 7.81.

EXAMPLE 2 Methyl 14-methyl-5,6-pyrazolinoA-nor-A andro stene-3-onel 7fi-carboxylate EXAMPLE 3 Methyl l4-methyl-5,6-pyrazolino-A-norandrostane- 1lB-ol-3-onel 7fi-carboxylate Following the procedure set forth in Example 1, but

substituting an equivalent amount of methyl 14-methyl-A- H nor-M-androstene-llB-ol-3-one 17,8 carboxylate for methyl 14 methyl-A-nor-A -androstene3,1l-dione-17,B- carboxylate, there is obtained methyl l4-methyl-5,6-pyrazolino-A-norandrostane-1 l [3-01-3 -one- 1 7fi-carboxylate.

EXAMPLE 4 max.

EXAMPLE 5 Methyl 6,14-dimethyl-A-nor-A -androstadiene-3- one- 1 7B-carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl 14-methyl- 5,6 pyrazolino-A-nor-A -androstene 17B carboxylate for methyl l4-methyl-5,6-pyrazolinoA-norandrostane-3,ll-dione-l7p-carboxylate, there is obtained methyl 6, 14-dimethyl-A-nor-A -androstadiene 3 one17flcarboxylate.

EXAMPLE 6 Methyl 6,14-dimethyl-A-nor-A -androstene--01-3- one- 1 7,8-carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl 14-methyl-5, 6-pyrazolino-A-nor-A- -androstene llfl ol-3-one-17,8-carboxylate for methyl 14-methyl-A-nor-A -androstene-3,20- dione-l7B-carboxylate, there is obtained methyl 6,14-dimethyl-A-nor-A -androstene-llB-ol 3 onel7,8-carboxylate.

EXAMPLE 7 '6,14-dimethyl-A-nor-A -androstene-3, l 1-dione-17flcarboxylic acid To a mixture of KOH in methanol and water, which has been refluxed for 10 minutes and cooled under a blanket of helium is added methyl 6,14-dimethyl-A-nor- A -androstene-3,1l-dione-l7fl-carboxylate and the resulting solution is refluxed under a blanket of helium. The mixture is then cooled and after the addition of glacial acetic acid is diluted with water. After the removal of the bulk of the methanol in vacuo the 6,14-dimethyl-A- nor-A -androstene3,ll-dione-l7B-carboxylic acid crystallizes and is filtered and washed with water.

EXAMPLE 8 6,l4-dimethyl-A-nor-A -androstadiene-3-one- 17,8-carboxylic acid Following the procedure set forth in Example 7 but substituting an equivalent amount of methyl 6,14-dimethyl A nor-A -androstadiene-3-one-l7fi-carboxylate for methyl 6,l4-dimethyl-A-nor-A -androstene-3,11 dione-17fi-carboxylate, there is obtained 6,14-dimethyl-A- nor-A -androstadiene-3-one-17B-carboxylic acid.

EXAMPLE 9 6, 14-dimethyl-A-nor-A -androstene-1 1,6-ol-3 -one- 19/3 carboxylic acid Following the procedure in Example 7 but substituting an equivalent amount of methyl 6,l4-dirnethyl-A-nor-A androstene-ll5-ol-3-one-17B-carboxylate for methyl 6,14- dimethyl-A-nor-A -androstene 3,11 dione-l'lfl-carboxylate, there is obtained 6,l4-dimethyl-A-nor-A -androstene-l l fi-ol-3 -0ne-19fi-carboxylic acid.

7 EXAMPLE 10 6,14-dimethyl-A-nor-A -androstene-3, 1 1-dione-17/3- carboxylic acid chloride To a suspension of vacuum dried 6,14-dimethyl-A-nor- A -androstene-3,1l-dione -17,8-carboxylic acid in anhydrous benzene is added with stirring redistilled oxalyl chloride. After 30 minutes all the acid has dissolved and the solution is allowed to remain at room temperature for an additional 40 minutes. Upon the removal of the solvent in vacuo there remains a crystalline solid to which is added anhydrous benzene and the latter removed again in vacuo, thus yielding 6,14-dimethyl-A-nor-A -androstene-3,11-dione-17B-carboxylic acid chloride.

EXAMPLE 1 1 6,14-dimethyl-A-nor-A -androstadiene-B-one- 17 ,B-carboxylic acid chloride Following the procedure set forth in Example 10 but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstadiene-3-one-l7/3-carboxylic acid for 6,14-dimethyl A nor-A -androstene-3,11-dione-17B-carboxylic acid there is obtained 6,14-dimethyl-A-nor-A androstadiene-3-one-17/8-carboxylic acid chloride.

EXAMPLE 12 6,14-dimethyl-A-nor-A -androstene-11,8-ol-3 -one-l7,8 carboxylic acid chloride Following the procedure set forth in Example 10 but substituting an equivalent amount of 6,14-dimethyl-A- n0r-A -androstene-11,8-ol-3-one 17fl-carboxylic acid for 6,14 dirnethyl-A-nor A -androsten-3,1l-dione-lZB-carboxylic acid there is obtained 6,14-dimethyl-A-nor-A androstene-llfl-ol-3-one-17,8-carboxylic acid chloride.

EXAMPLE 13 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3 ,1 1,20-

trione A solution of 6,14-dimethyl-A-nor-N-androstene-3,11- dione-17B-carboxylic acid chloride in anhydrous benzene is added at 0 C. to a concentrated distilled solution of diazomethane in ether. The mixture is allowed to warm up to room temperature and after a total reaction time of 1 hours it is filtered from flocculent polyethylene and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from methanol and furnishes 6,14-dimethyl 21 diazo A nor-A -pregnene-3,11,20- trione.

EXAMPLE 14 6,14-dimethyl-21-diazo-A-nor-A -pregnadiene- 3,20-dione Following the procedure set forth in Example 13 but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstadiene-3-one-17,8-carboxylic acid chloride for 6,14-dimethyl-A-nor-A -androstene 3,11 dione- 17.5-carboxylic acid chloride there is obtained 6,14-dimethyl-2l-diazo-A-n0r-A -pregnadiene-3,20-di0ne.

EXAMPLE 15 6, 14-dimethyl-21-diazo-A-nonM-pregnene-l 1 8-01- 3,20-dione Following the procedure set forth in Example 13 but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstene-11B-ol-3-one-17fl-carboxylic acid chloride for 6,14-dimethyl-A-nor-A -a-ndrostene-3,ll-dione- 17B-carboxylic acid chloride there is obtained 6,14-dimethyl-Z1-diazo-A-nor-A -pregnene-1 l,8-ol-3,20-dione.

EXAMPLE 16 6,14-dimethyl-21-chloro-A-nor-M-pregnene-3 ,11,20- trione To a solution of 6;,14-dimethyl-2l -diazo-A-nor-A pregnene-3,11,20-trione is added at 0 C. a saturated EXAMPLE 17 6,14-dimethyl-2l-chloro-A-nor-A -pregnadiene- 3,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of 6,14dimethyl-21- diazo-A-nor-A -pregnadiene-3-20-dione for 6,14-dimethyl-Zl-di'azo-A-nor-A -pregnene-3,11,20-trione there is obtained 6,14-dimethyl-21-chloro-A-nor-A -pregnadiene-3,20-dione.

EXAMPLE 18 6, l4-dimethyl-21-chl0ro-A-nor-A -pregnene- 11,B-ol-3,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of 6,14-dimethyl-21- diazo-A-nor-A -pregnene-11fl-o1-3,20-dione for 6,14-di methyl-2 1 -diazo-Anor-A -pregnene-3 1 1 ,20-trione there is obtained 6,14-dimethyl-21-chloro-A-n0r-A -pregnene- 11,B-ol-3,20-dione.

EXAMPLE 19 6,14-dirnethyl-A-nor-A -pregnene-3,1 1,20-trione To a solution of 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione in chloroform is added under a blanket of carbon dioxide freshly distilled aqueous hydriodic acid. The mixture is thoroughly mixed by shaking for 3 minutes at room temperature, poured into water and chloroform and the chloroform solution extracted with dilute sodium bicarbonate with the addition of a small amount of sodium bisulfite. The chloroform extract is then Washed with water, dried over sodium sulfate and evaporated to dryness in vacuo and the residue crystallized from methanol to yield 6,14-dimethyl-A-nor-M-pregnene-3,1l- ZO-trione.

EXAMPLE 20 6,14-dimethyl-A-nor-A -pregnadiene-3,20-dione Following the procedure set forth in Example 19 but substituting 6,14-dimethyl-21-diazo-A-nor-A -pregnadiene-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A pregnene 3,11,20 trione yields 6,14 dimethyl-A-nor- A -pregnadiene-3,20-dione.

EXAMPLE 21 6,14-dimethyl-A-nor-A -pregnene-11,8-01-3 ,20-dione Following the procedure set forth in Example 19 but substituting an equivalent amount of 6,14-dimethyl-21- diazo-A-nor-A -pregnene-11/3-ol-3,20-dione for 6,14-dimethyl-2 1-diazo-A-nor-A -pregnene-3 ,11,20-trione yields 6,14-dimethyl-A-nor-M-pregnene-1 1B-ol-3,20-dione.

EXAMPLE 22 6,14-dimethyl-A-nor-A -pregnene-21-01-3 ,11,20- trione-21-acetate A solution of 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione in glacial acetic acid is heated on the steam bath for /2 hour. Water and chloroform are added and the resulting chloroform extract washed with sodium bicarbonate and water, dried over sodium sulfate and the solvent evaporated to dryness in vacuo. The residual A -pregnadiene2 1*ol-3,20-dione-2 l-acetate.

EXAMPLE 24 6, l4-dimethyl-A-nor-A -pregnene-1 1,8,21-diol-3,20- dione-21-acetate Following the procedure set forth in Example 22 but substituting 6,14 dimethyl-21-diazoA-nor-A -pregnene- 11/3-ol-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A pregnene-3,l1,20-trione yields 6,14-dimethyl-A-nor-A pregnene-l1,8,21-dio1-3,20-dione-21-acetate.

EXAMPLE 25 6,14-dimethyl-A-nor-A -pregnene-21-01-3,11,20-trione To a solution of 6,14-dimethyl-A-nor-A -pregnene-21- ol-3,11,20-trione-21-acetate in methanol is added with stirring under nitrogen oxygen-free potassium carbonate. After 2 hours at room temperature glacial acetic acid is added and after the addition of water the methanol is removed in vacuo. The mixture is then extracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resultant crystallized 6,14-dimethyl-A-nor-n -pregnene-21-ol-3,11,20-trione is then recrystallized from acetone hexane.

EXAMPLE 26 6,14-dimethyl-A-r1or-A -pregnene-Z1-ol-3,20-dione Following the procedure set forth in Example 25 but substituting 6,14-dimethyl-A-nor-A -pregnadiene-21- ol-3,20-dione-21-acetate for 6,14-dimethyl-A-nonM-pregnene-21-ol-3,11,20-trione-2l-acetate there is obtained 6 14-dimethyl-A-nor-A -pregnene-21-ol-3,20-dione.

EXAMPLE 27 6,14-dimethyl-A-nor-A -pregnene-1 1fi,21-diol- 3,20-dione Following the procedure set forth in Example 25 but substituting 6,14-dimethyl-A-nor-A -pregnene-1 1p,2l-diol- 3,20-dione-2l-acetate for 6,l4-dimethyl-A-nor-A -pregnene-21-ol-3,11,20-trione-2l-acetate there is obtained 6, 14 dimethyl-A-nor-A -pregnene-21-01-3,l1,20-trione-2lacetate there is obtained 6,14-din1ethyl-A-nor-A -pregnene-l1fi,21-di0l-3,20-dione.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids of the formulae:

COOB

00013 (IJOOB R /\l/i /\1/\ IMO l Lu, W an, tH,

wherein B is selected from the group consisting of hydrogen and lower alkyl; X is lower alkyl; R is hydrogen; R is hydroxy; and together R and R is OX0 (0:).

2. Methyl 6,14 dimethyl A-nor-A -androstene-3,11- dione-17/3-carboxylate.

3. Methyl 6,14-dirnethyl-A-nor-A -androstadiene'-3- one-17j3-carboxylate.

4. Methyl 6,14-dirnethyl-A-nor-A -androstene-1113-01-3- one-l7fl-carboxylate.

References Cited UNITED STATES PATENTS 2/1965 Fried 260-239.5 9/1966 Fried 260-239.5

LEWIS GOTTS, Primary Examiner R. GERSTL, Assistant Examiner U.S. Cl. X.R. 260514R UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION N; 3'6OO'425 Dated August 17, 1971 Invcntofla) ef Fried It is certified that error appears in the above-identified patent And that 14 Letters Patent are hereby corrected as shown below COOB C OH should be:

Column 4, :fiormula "M" should be: V

Column 7, line 12, "latter should be: later;

mg UNITED STATES PATENT omcs' CERTIFICATE OF CORRECTION an: no; 3 Dated A g 17. 1971 Invaatorh) Josef Fried It is certified that error appears in the above-identified patent m3 that 16 Letters Patent are hereby counted as shown below:

Column l0, lines 2, 3 and 4 -.delete the phrase:

"there is obtained 6, acetate".

Signed and sealed this lhth day of March 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. Attesting Officer ROBERT GOT'ISCHALK Commissioner of Patents 

